Anesthesiology May 2024, Vol. 140, A13–A15.
The impact of bed rest on human skeletal muscle metabolism. Cell Rep Med 2024; 5:101372. PMID: 38232697.
Prolonged physical inactivity results in detrimental alterations in many physiologic processes including insulin insensitivity, but the kinetics and cellular mechanisms of these changes in human skeletal muscle are unknown. Healthy volunteers (8 female, 16 male) participating in aerospace research underwent a 60-day bed rest protocol with physiologic measurements and blood and skeletal muscle sampling at baseline and after 6 or 55 days. Intracellular glycogen accumulation, insulin insensitivity, and reduced glucose transporter (GLUT4) membrane localization occurred within 6 days but did not worsen further at a 55-day time point. In contrast, lipids associated with lipotoxicity (e.g,. ceramides, sphingomyelins) and inflammation continued to increase with a metabolic change from fatty acid to glucose oxidation. Plasma levels of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α were elevated after prolonged bed rest without changes in C-reactive protein or cortisol. Inactivity resulted in increased lipid droplets near mitochondria along with elongation of triglycerides and lipotoxic species that did not affect the protein components of the electron transport chain but resulted in fewer and smaller mitochondria accounting for a reduction in oxidative phosphorylation. Therefore, it is hypothesized that excessive nutrients enhance lipid-mediated mitochondrial damage whose reduced activity allows for further lipid accumulation in a detrimental feedback process.
Take home message: Reduced insulin sensitivity in skeletal muscle is an adaptation to prevent nutrient overload. Prolonged inactivity shifts fatty acid to glucose oxidation, increases lipotoxic and proinflammatory species, and reduces mitochondrial size. The imbalance of an elevated nutrient supply with concurrent reduced metabolic substrate may be a potential therapeutic target in the setting of prolonged physical inactivity.
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